1. Field of the Invention
The present invention relates to the field of optical imaging and therapeutics. More particularly, embodiments of the present invention provide minimally-invasive Fiberoptic Microneedle Devices (FMDs) for light-based therapeutics, which physically penetrate tissue and deliver light directly into the target area below the skin surface (FIG. 1). Embodiments of the invention enable depth-selective and deep photothermal therapeutics.
2. Description of the Related Art
A major limitation for bio-imaging, including optical imaging and therapeutics (such as hair removal or optical tomography techniques, such as OCT imaging), is the shallow penetration depth of light in turbid tissue such as skin. Due to both scattering and absorption of the laser's photons by inhomogeneous tissue structures within the epidermis and dermis such as cells, collagen fibers, and aqueous ground substance, it is difficult if not impossible to maintain a focused or collimated beam past 1 mm depth into tissue. In particular, due to photon scattering around water-encapsulated and water-containing cells, focused light penetration into subcutaneous tissue is prevented, rendering the maximum typical photonic penetration depth of only a few millimeters. Enhancing photonic delivery past this current barrier would enable more selective, deeper, light-based therapeutics and diagnostics.
Currently, light-based therapeutics including oncology treatments, dermatology treatments, cosmetic surgeries, and alternative medicine protocols are limited in the results achieved and/or are not desirable by patients due to the pain typically associated with current procedures for performing these treatments. More specifically, applications that could benefit from improved light-based therapeutics (in particular, increased light penetration in skin) include a broad range of therapeutics ranging from the treatment of deep skin cancers such as melanoma to cosmetic procedures such as laser hair removal, especially for darker-skinned patients. By reaching targets beneath the skin surface, such as blood vessels, hair follicles, subdermal fat, and tattoo particles, to name a few, laser-based therapies and cosmetic applications including skin tightening, wrinkle removal, body contouring (fat reshaping or removal), and cellulite reduction could be substantially improved.
For example, minimally invasive laser-based hyperthermia therapy of cancers under the skin, such as melanoma, is currently not feasible due to the shallow penetration of light past the tumor surface. Such therapeutics could be feasible, however, by delivering light several millimeters deep in the tumor. By directly delivering optical radiation in near proximity to target tissue by way of minimally invasive optical fiber needles, the optical dose can be more precise, reducing unwanted collateral tissue damage and associated pain, and faster wound healing (with less scarring and bleeding) can be achieved. Increasing the amount of light penetration could also lead to the detection (and treatment) of tumors located several millimeters beneath the skin's surface through the use of laser-based methods.
Previous research has demonstrated that the light penetration problem can be overcome by using optical fibers to mechanically penetrate skin tissue for the purposes of transmitting light into desired areas. See Prudhomme, M., et al., 1996, “Interstitial Diode Laser Hyperthermia in the Treatment of Subcutaneous Tumor,” Lasers in Surgery and Medicine, 19(4), pp. 445-450, the disclosure of which is incorporated by reference herein in its entirety.
Additionally, it has been known to place a silica optical fiber inside a 3.05 mm thick metal cannula with a light diffusing cap made from quartz. Robinson, D. S., et al., 1998, “Interstitial Laser Hyperthermia Model Development for Minimally Invasive Therapy of Breast Carcinoma,” Journal of the American College of Surgeons, 186(3), pp. 284-292, the disclosure of which is incorporated by reference herein in its entirety. This design was used to deliver 1064 nm Nd:YAG laser light several centimeters deep into breast tumors.
Vertical cavity surface emitting lasers (VCSELs) are also known. For example, U.S. Pat. No. 7,027,478, entitled “Microneedle Array Systems,” the disclosure of which is incorporated by reference herein in its entirety, discloses a device comprising an array of hollow microneedles that are 250 microns in length and have an entrance hole that is 175-200 microns in diameter and an exit hole diameter of 125 microns. Within the hollow portion of the needle (the interior channel) an optical fiber is placed for transmission of light through the needle (which is made of metal and is prepared using photolithography or laser drilling, or is made of high-temperature plastic). Such needles are large and could cause unnecessary damage if inserted into skin. Further, the disclosure does not support extending the technology to smaller needles, and is silent on using additional support means for supporting and guiding the needles during insertion into skin, due to the needles themselves being made of a material (metal or plastic) and having a configuration (large) the combination of which provides sufficient strength to the needles themselves.
Other probe designs were developed for use in diagnostic methods such as optical coherence tomography and optical spectroscopy. See Li, X. D., et al., 2000, “Imaging Needle for Optical Coherence Tomography,” Optics Letters, 25(20), pp. 1520-1522; and Utzinger, U., and Richards-Kortum, R. R., 2003, “Fiber Optic Probes for Biomedical Optical Spectroscopy,” Journal of Biomedical Optics, 8(1), pp. 121-147, the disclosures of both of which are incorporated by reference herein in their entireties. The fiberoptic probes used in these studies, however, are on the order of 300 μm to several millimeters in diameter. See, e.g., Robinson 1998; Prudhomme 1996; Li 2000; and Mumtaz, H., et al. 1996, “Laser Therapy for Breast Cancer: Mr Imaging and Histopathologic Correlation,” Radiology, 200(3), pp. 651-658, the disclosure of which is incorporated by reference herein in its entirety.
With respect to physically penetrating skin (e.g., by mechanical means), while reducing or eliminating pain typically encountered by patients undergoing these procedures, it would be desirable to follow a pain-free microneedle model provided in nature—the mosquito fascicle. A mosquito has evolved to penetrate the skin with a flexible biological needle that is extremely small and flexible, inserting it into the skin to draw a meal of blood. The subsequent irritation caused by a mosquito bite is due to the allergic reaction to the saliva that the mosquito secretes during the blood draw to prevent platelet aggregation, not due to the needle insertion itself. See, Ribeiro, J. M. C. and I. M. B. Francischetti, “Role of arthropod saliva in blood feeding: Sialome and post-sialome perspectives,” Annual Review of Entomology, 2003, 48: pp. 73-88, the disclosure of which is incorporated by reference herein in its entirety.
Mosquito-performed blood extraction is done through the fascicle which is covered by an outer sheath called the labium. An SEM photograph of a fascicle tip protruding from the end of the partially retracted labium is shown in FIG. 2. See, Ramasubramanian, M. K., et al., “Mechanics of a mosquito bite with applications to microneedle design,” Bioinspiration & Biomimetics, 2008, 3(4), the disclosure of which is incorporated by reference herein in its entirety. The dimensions of the mosquito fascicle are typically 1.8 mm long with a 40 μm outer diameter. The tip of the fascicle is very sharp, tapering from about 10 μm to less than 1 μm over the last 50 μm of the fascicle. The fascicle is a polymeric microneedle composed of a ductile material, chitin, with an elastic modulus between 10 and 200 GPa (Ramasubramanian 2008) (similar to the inventive silica microneedles). The critical buckling load for a typical fascicle alone is very low (˜3 mN) and not sufficient to penetrate the skin (>10 mN required); however, the lateral support provided by the labium increases the critical buckling load by a factor of 5 and permits successful skin penetration.
Buckling is the most common mode of failure for slender objects forced along their axial direction. This is true for silica-fiber-based fiberoptic microneedles as well. Increasing the buckling force of light guiding needles having a length/diameter ratio of approximately 50 is a challenge. The critical buckling force of a straight cylindrical column with fixed ends can be approximated using Euler's equation. See, Wang, C. M., Wang C. Y., Reddy, J. N., “Exact Solutions for Buckling of Structural Members,” CRC Series in Computational Mechanics and Applied Analysis, 2004, the disclosure of which is incorporated by reference herein in its entirety.
A microneedle 2 mm long can safely penetrate skin if its diameter is larger than about 150 μm, which is close to the size of a wood splinter or a standard optical fiber, which are both known to penetrate the skin and inflict some level of pain. As shown in FIG. 3, the critical buckling force of silica microneedles (E=73 GPa for silica) with 2 mm unsupported length is plotted vs. diameter, and, for comparison, the penetration force required for microneedle insertion into skin obtained from results by Davis et al. is also shown. See, Davis, S. P., et al., “Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force,” Journal of Biomechanics, 2004, 37(8): p. 1155-1163, the disclosure of which is incorporated by reference herein in its entirety.
In order to improve the feasibility of using much smaller, less invasive nano- and micro-needles in clinical applications, the critical buckling force of the needles must be improved. Enhancing photonic transmission depth without absorption and scattering to allow imaging and light-based therapeutics below the epidermis (top 100 μm) and dermis (1-2 mm thick below epidermis) would have important implications in basic research (individual cell imaging), tissue engineering, and tissue therapeutics.
What is needed, and what embodiments of the present invention provide, are thinner fiberoptic microneedles (140 μm or less in diameter) for substantially reducing the morbidity and associated pain caused by insertion of needles into living tissue.